JP2015067538A - Hypoglycemic agent - Google Patents
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本発明は、アマドコロ由来の化合物を有効成分として含む血糖値降下剤に関する。 The present invention relates to a hypoglycemic agent comprising a compound derived from Amadocoro as an active ingredient.
糖尿病は糖代謝異常によるものであり、さらには高血糖により様々な合併症を引き起こす病である。厚生労働省の発表（２０１１年国民健康・栄養調査報告）では、我が国において成人の４人に１人が糖尿病もしくはその予備群であるとされ、深刻さを増している。糖尿病は、過食や偏食、運動不足などの生活習慣の乱れが原因の一つであり、発症すると完全に完治する事が難しい。そこで日常的に予防し、発症リスクを低減させる事が望まれており、その一つの方法として血糖値降下作用を有する食品の摂取がある。 Diabetes mellitus is caused by abnormal glucose metabolism, and further causes various complications due to hyperglycemia. According to an announcement by the Ministry of Health, Labor and Welfare (2011 National Health and Nutrition Survey Report), one out of every four adults in Japan is considered to be diabetic or its reserve group, which is becoming more serious. Diabetes is one of the causes of lifestyle disturbances such as overeating, unbalanced diet, and lack of exercise, and it is difficult to completely cure once it develops. Therefore, it is desired to prevent it on a daily basis and reduce the risk of onset, and as one of the methods, there is intake of food having a blood glucose level lowering effect.
上記理由より、安全性が高く、且つ糖尿病の予防が可能な食品の開発が望まれるが、本発明者らはこの要望を満たす食品の開発を実現する為に、中医学で使用される生薬に着目した。 For the above reasons, it is desired to develop a food that is highly safe and can prevent diabetes.In order to realize the development of a food that satisfies this demand, the present inventors have developed a herbal medicine used in Chinese medicine. Pay attention.
まず以下に中医学およびその中医学における生薬の分類について説明する。中医学は、病気を発症する前段階である「未病」の状態に対し、処置を行い、病気の発症を防ぐ理論を有している。特に生薬の利用方法に優れており、長い年月を掛けて体験的に実証確立され、さらに安全性や効き目の強さから「上薬」、「中薬」、「下薬」に分類されている。 First, the classification of Chinese medicine and herbal medicine in the Chinese medicine will be explained below. Chinese medicine has the theory that it treats the state of “non-disease”, which is the stage before the onset of the disease, and prevents the onset of the disease. It is particularly excellent in the use of crude drugs, has been established through empirical verification over a long period of time, and is further classified into `` superior '', `` medicated '', and `` laxative '' based on safety and strength of efficacy. Yes.
「上薬」は、長期間服用しても副作用がなく、かつ効果が期待できる生薬のグループである。本発明者らは、そのグループの中から糖尿病の症状にも利用され、かつ食品として食経験の豊富なアマドコロに注目した。 “Epic medicine” is a group of herbal medicines that have no side effects even when taken for a long time and can be expected to be effective. The present inventors paid attention to Amadocoro, which is also used for diabetes symptoms and has a rich dietary experience as food.
アマドコロは、ユリ科アマドコロ属の多年草であり、山菜として根茎や新芽が食されている。近年の研究ではアマドコロの特徴的な生理活性としてインスリン抵抗性を緩和する事により血糖値降下作用を示す事が報告されている（非特許文献１）。また同じユリ科アマドコロ属の近縁種であるナルコユリから単離されたスピロスタノール型サポニンに血糖値降下活性が確認されており、アマドコロにも含まれている事が報告されている（非特許文献２〜３）。しかしアマドコロには、スピロスタノール型サポニン以外の特異的な血糖値降下活性化合物の存在が示唆されており、その化合物は単離同定されていない。よってアマドコロの生理活性化合物に関しては、未だ未解明な部分が多いのが現状である。 Amadokoro is a perennial plant belonging to the genus Amadokoro in the lily family, and roots and shoots are eaten as wild plants. In recent studies, it has been reported that the blood glucose level lowering action is shown by relieving insulin resistance as a characteristic physiological activity of Amadokororo (Non-patent Document 1). In addition, spirostanol-type saponins isolated from Narcoli, a related species of the same genus Amadokoro, have been confirmed to have a hypoglycemic activity and have also been reported to be contained in Amadokoroko (non-patent literature) 2-3). However, it has been suggested that Amadochoro has a specific antihyperglycemic compound other than spirostanol-type saponin, and the compound has not been isolated and identified. Therefore, there are still many unexplained parts regarding the bioactive compounds of Amadocoro.
本発明は、アマドコロ由来の血糖値降下作用を有する化合物を含有し、食品として摂取可能な血糖値降下剤を提供する。 The present invention provides a hypoglycemic agent which contains a compound having a hypoglycemic effect derived from Amadocoro and can be taken as a food.
前記課題を解決するための手段としては、以下の通りである。
＜１＞下記構造式（１）で表わされる化合物を有効成分として含む血糖値降下剤である。
<1> A hypoglycemic agent comprising a compound represented by the following structural formula (1) as an active ingredient.
＜２＞アマドコロの抽出物であって、前記＜１＞に記載の化合物を有効成分として含む血糖値降下剤である。 <2> Amadochoro extract, which is a hypoglycemic agent comprising the compound according to <1> as an active ingredient.
本発明により、アマドコロ由来の血糖値降下作用を有する化合物を有効成分として含む食品等の提供が可能となる According to the present invention, it is possible to provide a food or the like containing a compound having a blood glucose level-lowering effect derived from Amadocoro as an active ingredient.
以下に本発明の実施の形態を詳細に説明する。 Hereinafter, embodiments of the present invention will be described in detail.
本発明は、アマドコロ由来の血糖値降下作用を有する化合物を有効成分として含有する血糖値降下剤に関する。 The present invention relates to a hypoglycemic agent comprising a compound having a hypoglycemic activity derived from Amadocoro as an active ingredient.
本発明の血糖値降下剤は、アマドコロ由来の前記構造式（１）で表される化合物を含有すればよい。原料となるアマドコロの生産地や品種は、特に制限されず、根茎や葉、茎、果実、花を含む全草のいずれも用いてよいが、好ましくは根茎を用いる。またそれらの部位は、生鮮物もしくは乾燥物のいずれを用いても良い。 The hypoglycemic agent of the present invention may contain a compound represented by the structural formula (1) derived from Amadocoro. There are no particular restrictions on the production area or variety of Amadocorro as a raw material, and any of the whole plants including rhizomes, leaves, stems, fruits, and flowers may be used, but rhizomes are preferably used. In addition, those parts may be either fresh or dried.
以下に前記構造式（１）で表される化合物の抽出および精製方法を記す。 A method for extracting and purifying the compound represented by the structural formula (1) will be described below.
本発明に用いるアマドコロの抽出方法は特に制限はないが、抽出に用いるアマドコロは破砕、粉砕等により粉末化処理したものが好ましい。抽出条件は特に制限されないが、水もしくは親水性アルコール、またはその混合物を用いて抽出を行う。アルコールの例としてメタノール、エタノール、１―ブタノール、２−ブタノール、１−プロパノール、イソプロパノール等が挙げられるが、特にメタノールが好ましい。 There is no particular limitation on the method for extracting the amadocho used in the present invention, but the amadocho used for the extraction is preferably pulverized, pulverized or the like. Although extraction conditions are not particularly limited, extraction is performed using water, hydrophilic alcohol, or a mixture thereof. Examples of the alcohol include methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, isopropanol and the like, and methanol is particularly preferable.
抽出する際の温度は特に限定されず、室温もしくは過熱して抽出する。抽出時間は、溶剤によって異なるが、メタノールで抽出する場合は、１〜２時間程度が好ましい。また抽出に用いる溶剤量は、原料に対し１〜２０倍量が好ましい。 The temperature at the time of extraction is not specifically limited, It extracts by room temperature or heating. Although extraction time changes with solvents, when extracting with methanol, about 1-2 hours are preferable. The amount of solvent used for extraction is preferably 1 to 20 times the amount of the raw material.
抽出後は、ろ過あるいは遠心分離等により抽出残渣を取り除き、減圧濃縮等により溶剤を除去する事で本発明の化合物を含む抽出物（エキス）を得る事ができる。 After the extraction, the extract residue containing the compound of the present invention can be obtained by removing the extraction residue by filtration or centrifugation and removing the solvent by vacuum concentration or the like.
前記の抽出および精製方法により得られたエキスは糖類や油脂類などの夾雑物が多く含まれているが、分配クロマトグラフィー等を行う事で除去する事ができる。例えば水と１−ブタノールを用いて分配クロマトグラフィーを行うと、糖類は水層へ移行し、本発明の化合物は、１−ブタノール層に移行する。１−ブタノール層を乾固し、得られた１−ブタノール可溶部をヘキサン等で脱脂処理を行う事で本発明の化合物を高濃度に含む粗精製物を得る事ができる。 The extract obtained by the extraction and purification method described above contains a large amount of contaminants such as sugars and fats and oils, but can be removed by partition chromatography or the like. For example, when partition chromatography is performed using water and 1-butanol, the saccharide moves to the aqueous layer, and the compound of the present invention moves to the 1-butanol layer. By roughening the 1-butanol layer and subjecting the obtained 1-butanol soluble part to degreasing treatment with hexane or the like, a crude product containing the compound of the present invention at a high concentration can be obtained.
さらに前記の粗精製物を順相カラムや逆相カラム、ゲルろ過カラム等を用いた各種クロマトグラフィーや再結晶等の操作を行うことで、本発明の化合物を単離精製することができる。 Furthermore, the compound of the present invention can be isolated and purified by performing various operations such as chromatography and recrystallization using a normal phase column, reverse phase column, gel filtration column and the like on the crude product.
上記の操作で得られる抽出物や精製物は、いずれも食品として利用可能であり、食品形状は特に限定されない。 Any of the extracts and purified products obtained by the above operations can be used as food, and the shape of the food is not particularly limited.
以下に実施例を挙げて本発明を詳細に説明するが、本発明は実施例になんら限定されるものではない。 Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to the examples.
アマドコロ由来の血糖値降下活性化合物を単離同定する方法として、血糖値降下活性評価試験を指標にして分離精製を試みた。まず血糖値降下活性評価試験について以下に説明する。 As a method for isolating and identifying a blood sugar level lowering activity compound derived from Amadocoro, separation and purification were attempted using a blood glucose level lowering activity evaluation test as an index. First, the blood glucose level lowering activity evaluation test will be described below.
（血糖値降下活性評価試験方法）
７週齢のＫＫ−Ａｙの系雄マウス（インスリン非依存性糖尿病モデルマウス）を日本クレア株式会社から購入し、約２週間の予備飼育後、試験に使用した。マウスを約１７時間絶食した後、血糖値を測定し、群間で血糖値にばらつきが生じないように群分けを行った。試験群あたりのマウス数は６匹とした。採血は、外側尾静脈より採血し、アキュチェックアビバ（ロシュ・ダイアグノスティックス株式会社）を用いて血糖値の測定を行った。
評価するアマドコロ由来のサンプルは、濃度５ｍｇ／ｍｌとなるように生理食塩水に溶解して調整した。マウス体重に対し、サンプル投与量が１００ｍｇ／ｋｇとなるように投与容量は２０ｍｌ／ｋｇとした。効果をより鮮明に確認する為、腹腔内投与にて行った。投与時の血糖値を測定し、投与１０時間後に再度血糖値を測定し、血糖値の減少量を求めた。評価は、対照群である生理食塩水投与群の血糖値減少量と比較する事で行った。
(Glucose level lowering activity evaluation test method)
Seven-week-old KK-Ay male mice (insulin-independent diabetes model mice) were purchased from CLEA Japan, and used for the test after preliminary breeding for about 2 weeks. After the mice were fasted for about 17 hours, blood glucose levels were measured and divided into groups so that blood glucose levels did not vary between groups. The number of mice per test group was 6. Blood was collected from the lateral tail vein and the blood glucose level was measured using Accu Check Aviva (Roche Diagnostics Inc.).
The sample derived from Amadocoro to be evaluated was prepared by dissolving in physiological saline so as to have a concentration of 5 mg / ml. The dose volume was 20 ml / kg so that the sample dose was 100 mg / kg relative to the mouse body weight. In order to confirm the effect more clearly, intraperitoneal administration was performed. The blood glucose level at the time of administration was measured, and the blood glucose level was measured again 10 hours after the administration to determine the amount of decrease in the blood glucose level. The evaluation was performed by comparing with a decrease in blood glucose level in the physiological saline administration group as a control group.
次に、前記の血糖値降下活性評価試験を指標にしたアマドコロ由来の血糖値降下活性化合物の単離同定について説明する。 Next, the isolation and identification of the Amadocoro-derived blood glucose level lowering activity compound using the blood glucose level lowering activity evaluation test as an index will be described.
（血糖値降下活性化合物の単離同定）
アマドコロの根茎の乾燥粉末２ｋｇを、メタノール３Lを用いて１．５時間、加熱抽出を３回行い、メタノール抽出液を得た。抽出液は、溶剤を留去し、メタノール抽出物４５２ｇを得た。次にメタノール抽出物を水と１−ブタノールを用いた分配クロマトグラフィーに供し、１−ブタノール層を回収後、溶剤を留去し、得られた１−ブタノール可溶部をn―ヘキサンで脱脂処理してサポニン画分１０．４ｇを得た。
前記のとおり得られたサポニン画分を前記の血糖値降下活性評価試験に供したところ、図1に示すように生理食塩水のみを投与した対照群に比べ血糖値の低下が見られたため、サポニン画分をシリカゲルカラム（シリカゲル６０、１５４ｇ）に供し、吸着後、クロロホルム／メタノール／水の混合溶媒（＝１０：２：０．１、７：３：０．５、５：５：０．５、０：１０：０）の各１Ｌを用いて順次溶出して分取した。分取した画分を再度血糖値降下活性評価試験に供したところ、Ｅｈｒｌｉｃｈ試薬で発色する画分（以後、Ｅｈｒｌｉｃｈ試薬陽性画分）に活性が見られたため（図１）、Ｅｈｒｌｉｃｈ試薬陽性の化合物をターゲットにし、以後の精製を進めた。
前記のとおり得られたＥｈｒｌｉｃｈ試薬陽性画分９４２ｍｇをゲルろ過カラム（Ｓｅｐｈａｄｅｘ ＬＨ−２０、ゲル体積１１９ｍｌ）に供し、メタノールで溶出し、Ｅｈｒｌｉｃｈ試薬で発色する画分６９５ｍｇを分取した。得られた画分の一部３０ｍｇをＨＰＬＣ（ＹＭＣ−Ｐａｃｋ ＯＤＳ−ＡＭ、２５０×２０ｍｍＩ．Ｄ．）に供し、７０％メタノールで溶出して、Ｅｈｒｌｉｃｈ試薬陽性の化合物２５ｍｇを単離した。
単離したＥｈｒｌｉｃｈ試薬陽性化合物を前記の血糖値降下活性評価試験に供したところ、図１に示すように生理食塩水のみを投与した対照群に比べ、有意（Ｐ＜０．０５）に血糖値降下活性が認められたため、１Ｈ―ＮＭＲおよび１３Ｃ―ＮＭＲ、ＭＳの測定を行い、構造解析を試みた。その結果、得られたスペクトル値がアマドコロから単離（小野ら、生薬学雑誌 ４２（２）、１３５−１４２（１９９８））の報告があるフルスタノール形サポニンＰＯ−７と文献値が一致したため、ＰＯ−７と同定した。これまでにＰＯ−７は、血糖値降下活性は報告されておらず、本発明者らによって初めて見出された。
(Isolation and identification of hypoglycemic active compounds)
A 2 kg dry powder of Amadokororo rhizome was subjected to heat extraction three times for 1.5 hours using 3 L of methanol to obtain a methanol extract. In the extract, the solvent was distilled off to obtain 452 g of a methanol extract. Next, the methanol extract was subjected to partition chromatography using water and 1-butanol, the 1-butanol layer was recovered, the solvent was distilled off, and the resulting 1-butanol soluble part was degreased with n-hexane. As a result, 10.4 g of a saponin fraction was obtained.
When the saponin fraction obtained as described above was subjected to the blood glucose level lowering activity evaluation test, a decrease in blood glucose level was observed as compared to the control group administered with only physiological saline as shown in FIG. The fraction was applied to a silica gel column (silica gel 60, 154 g), and after adsorption, a mixed solvent of chloroform / methanol / water (= 10: 2: 0.1, 7: 3: 0.5, 5: 5: 0.5). , 0: 10: 0), and then eluted and fractionated sequentially. When the collected fraction was again subjected to the blood glucose level lowering activity evaluation test, activity was observed in the fraction that developed color with the Ehrrich reagent (hereinafter, Ehrrich reagent positive fraction) (FIG. 1). The following refinement was advanced.
942 mg of the Ehrrich reagent positive fraction obtained as described above was applied to a gel filtration column (Sephadex LH-20, gel volume 119 ml), eluted with methanol, and 695 mg of a fraction colored with the Ehrrich reagent was collected. A 30 mg portion of the obtained fraction was subjected to HPLC (YMC-Pack ODS-AM, 250 × 20 mm ID) and eluted with 70% methanol to isolate 25 mg of Ehrlich reagent positive compound.
When the isolated Ehrrich reagent-positive compound was subjected to the blood glucose level lowering activity evaluation test, as shown in FIG. 1, the blood glucose level was significantly (P <0.05) compared to the control group administered with only physiological saline. Since the lowering activity was observed, 1 H-NMR, 13 C-NMR, and MS were measured, and a structural analysis was attempted. As a result, the spectrum value obtained was isolated from Amadokororo (Ono et al., Biopharmaceutical Journal 42 (2), 135-142 (1998)), and the document value was in agreement with the frustanol-type saponin PO-7. Identified as PO-7. So far, PO-7 has not been reported to have a hypoglycemic activity and has been found for the first time by the present inventors.
Claims (2)
A hypoglycemic agent which is an extract of Amadochoro and contains the compound according to claim 1 as an active ingredient.
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| ＣＨＥＭＩＣＡＬ ＆ ＰＨＡＲＭＡＣＥＵＴＩＣＡＬ ＢＵＬＬＴＥＩＮ, vol. Ｖｏｌｕｍｅ４２、Ｉｓｓｕｅ４, JPN6017013954, 1994, pages ｐ．９２６−９３１ * |
| ＪＯＵＲＮＡＬ ＯＦ ＥＴＨＮＯＰＨＡＲＭＡＣＯＬＯＧＹ, vol. Ｖｏｌｕｍｅ１４１、Ｉｓｓｕｅ１, JPN6017013953, May 2012 (2012-05-01), pages ｐ．２２８−２３３ * |
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